Aqueous-deficient dry eye (ADDE) is among the most common and debilitating clinical manifestations of systemic autoimmune diseases such as Sjgren's syndrome (SS) for which there is no cure. While it is well established that chronic inflammation represents a predominant driving force in ADDE, an important yet often overlooked component of ADDE is altered innervation of the cornea and lacrimal gland. Loss of neuronal inputs upsets the complex reflex network connecting the ocular mucosal tissues (e.g. cornea, limbus, conjunctiva) and the tear secreting machinery (e.g. lacrimal glands) that maintains ocular surface and glandular epithelial homeostasis. Yet, despite the essential need for a functional nerve supply, current medications and therapeutic strategies do not address the importance of maintaining and/or reinnervating ocular tissues. As such, it is essential to identify new therapies that possess neuroregenerative and pro- secretory properties to restore ocular health in ADDE. In this proposal we define the impact of a novel therapeutic, lacripep, on maintaining/promoting functional innervation of the cornea and lacrimal gland. Lacripep is the active component of lacritin, a naturally occurring glycoprotein in human tears with prosecretory and mitogenic properties. Recently, we reported reduced levels of lacritin in the tears of human patients with SS and discovered that topical application of lacritin promoted tear secretion, improved corneal epithelial integrity and reduced inflammation in an autoimmune-regulator (Aire)-deficient mouse model of SS-associated ADDE. In our preliminary studies using this model we show lacripep not only promotes tear production but also rescues innervation of the cornea and lacrimal glands, thus restoring an essential component of ocular homeostasis. Based on these studies, we propose to determine the impact of lacripep on corneal and lacrimal gland innervation during ADDE development, as well as defining mechanisms by which lacripep maintains and/or restores innervation. Thus, the goals of this proposal are to: Aim 1) Define the neuroregenerative potential of lacripep in the cornea and lacrimal gland during dry eye disease progression; Aim 2) Define the mechanisms by which lacripep achieves functional innervation of the cornea during the development of dry eye; and Aim 3) Determine if lacripep restores tear secretion by preferentially increasing functional parasympathetic innervation of the lacrimal gland. Using a combination of imaging, biochemical and genetic approaches, the proposed studies will considerably advance our understanding of the mechanisms by which loss of corneal innervation and secretory function occurs as well as the functional significance of denervation on disease progression. With 95% of dry eye patients selectively deficient in lacritin, topical use of lacripep as a natural replacement therapy for dry eye presents a tremendous opportunity to fill an enormous void in the clinical management of these patients.